Our proposal is designed to characterize the electrical heterogeneity intrinsic to the atrial and ventricular myocardium, to which our group has contributed significantly over the past many years. Our specific aims are to: 1) probe differences in sodium channel and action potential characteristics of atrial vs. ventricular cells isolated from the canine heart and assess how these distinctions contribute to atrial-selective sodium channel inhibition and suppression of atrial fibrillation by INa blockers;2) determine to what extent the electrical and pharmacologic heterogeneities uncovered in the canine right atrium exist in the left atrium;3) determine to what extent electrical and pharmacologic heterogeneities uncovered in canine right and left atria of normal dogs differ from those of respective tissues and cells isolated from heart failure dogs (HF); 4) assess the propensity for the development of atrial fibrillation in atria isolated from heart failure dogs and define the substrate and triggers that underlie arrhythmogenesis. 5) assess the effectiveness of different classes of sodium channel blockers in terminating and suppressing re-induction of AF, determine to what extent these agents are atrial-selective, and the mechanisms involved;6) probe the basis for atrial-selective sodium channel block responsible for the anti-AF effects of sodium channel blockers in HF dogs;and 7) assess the influence of parasympathetic agonists on the development of AF in atria isolated from normal and heart failure dogs. The principal goals of our proposal are to probe the extent to which electrical heterogeneities exist between the right and left atrium and ventricles of the canine heart and examine how amplification of these heterogeneities contributes to the development of atrial and ventricular arrhythmias in the normal heart as well as in structurally compromised hearts isolated from dogs with pacing-induced dilated cardiomyopathy. The proposed project is a clinically relevant research inquiry designed to advance our understanding of atrial arrhythmia development and approach to therapy. The central focus involving a test of the hypothesis that atrial-selective modulation of the sodium channel can prevent AF without significantly altering ventricular electrophysiology is innovative and exciting and has the potential to produce a paradigm shift in the pharmacologic approach to therapy of AF, one of the greatest unmet medical needs facing our society. Successful completion of the project will also identify the ionic and cellular mechanisms that contribute to atrial selectivity, thus creating a unique platform for the development of novel therapies that could potentially find their way to the bedside. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in the clinic, affecting an estimated 2.5 million Americans. Its prevalence is age-related and is increasing sharply with aging of the population, to the point where the term epidemic has been applied. AF is a major complication associated with congestive heart failure (CHF), which affects an estimated 5 million patients in the United States and is a major cause of hospitalization and mortality. Currently available therapeutic options all have intrinsic limitations and new approaches to the pharmacologic management of atrial fibrillation are critically needed. Safe and effective pharmacologic treatment for AF is one of the greatest unmet medical needs facing our society. Successful completion of the studies proposed in this competing renewal will significantly advance this goal and lead to the development of innovative and effective pharmacologic treatments for AF.